Combinatorial, additive and dose-dependent drug-microbiome associations.

During the transition from a healthy state to cardiometabolic disease, patients become heavily medicated, which leads to an increasingly aberrant gut microbiome and serum metabolome, and complicates biomarker discovery1-5. Here, through integrated multi-omics analyses of 2,173 European residents from the MetaCardis cohort, we show that the explanatory power of drugs for the variability in both host and gut microbiome features exceeds that of disease. We quantify inferred effects of single medications, their combinations as well as additive effects, and show that the latter shift the metabolome and microbiome towards a healthier state, exemplified in synergistic reduction in serum atherogenic lipoproteins by statins combined with aspirin, or enrichment of intestinal Roseburia by diuretic agents combined with beta-blockers. Several antibiotics exhibit a quantitative relationship between the number of courses prescribed and progression towards a microbiome state that is associated with the severity of cardiometabolic disease. We also report a relationship between cardiometabolic drug dosage, improvement in clinical markers and microbiome composition, supporting direct drug effects. Taken together, our computational framework and resulting resources enable the disentanglement of the effects of drugs and disease on host and microbiome features in multimedicated individuals. Furthermore, the robust signatures identified using our framework provide new hypotheses for drug-host-microbiome interactions in cardiometabolic disease.

Statin therapy is associated with lower prevalence of gut microbiota dysbiosis.

Microbiome community typing analyses have recently identified the Bacteroides2 (Bact2) enterotype, an intestinal microbiota configuration that is associated with systemic inflammation and has a high prevalence in loose stools in humans1,2. Bact2 is characterized by a high proportion of Bacteroides, a low proportion of Faecalibacterium and low microbial cell densities1,2, and its prevalence varies from 13% in a general population cohort to as high as 78% in patients with inflammatory bowel disease2. Reported changes in stool consistency3 and inflammation status4 during the progression towards obesity and metabolic comorbidities led us to propose that these developments might similarly correlate with an increased prevalence of the potentially dysbiotic Bact2 enterotype. Here, by exploring obesity-associated microbiota alterations in the quantitative faecal metagenomes of the cross-sectional MetaCardis Body Mass Index Spectrum cohort (n = 888), we identify statin therapy as a key covariate of microbiome diversification. By focusing on a subcohort of participants that are not medicated with statins, we find that the prevalence of Bact2 correlates with body mass index, increasing from 3.90% in lean or overweight participants to 17.73% in obese participants. Systemic inflammation levels in Bact2-enterotyped individuals are higher than predicted on the basis of their obesity status, indicative of Bact2 as a dysbiotic microbiome constellation. We also observe that obesity-associated microbiota dysbiosis is negatively associated with statin treatment, resulting in a lower Bact2 prevalence of 5.88% in statin-medicated obese participants. This finding is validated in both the accompanying MetaCardis cardiovascular disease dataset (n = 282) and the independent Flemish Gut Flora Project population cohort (n = 2,345). The potential benefits of statins in this context will require further evaluation in a prospective clinical trial to ascertain whether the effect is reproducible in a randomized population and before considering their application as microbiota-modulating therapeutics.

Arterial Thromboembolism in Patients With Atrial Fibrillation and CHA2DS2-VASc Score 1: A Nationwide Study.

BACKGROUND: Oral anticoagulation is suggested in patients with atrial fibrillation and a CHA2DS2-VASc score ≥1 (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke, vascular disease, age 65-74 years, and sex score). To assess granular differences within CHA2DS2-VASc 1, the incidence of arterial thromboembolism according to CHA2DS2-VASc 1 subgroups was examined. METHODS: The Danish National Patient Registry and the Danish Prescription Registry were linked on a nationwide level to identify patients with atrial fibrillation from 2000 to 2021 without oral anticoagulation and categorized according to CHA2DS2-VASc score: CHA2DS2-VASc 0 (male and female subjects); CHA2DS2-VASc 1 (hypertension, heart failure, diabetes, vascular disease, and age 65-74 years); or CHA2DS2-VASc 2 (age ≥75 years without other risk factors). Female sex was not considered a risk factor in any risk group. The outcome was arterial thromboembolism (ischemic stroke, embolism of extremity, or transient cerebral ischemia). Study groups were compared using Cox regression analysis. RESULTS: We included 26 701 patients with a CHA2DS2-VASc 0 score; 22 915 with CHA2DS2-VASc 1 (1483 patients with heart failure, 9066 with hypertension, 843 with diabetes, 770 with vascular disease, and 10 753 who were 65 to 74 years of age); and 14 525 patients with CHA2DS2-VASc 2 (≥75 years of age without other risk factors). With a median of 1 year of observation time, the cumulative incidence of arterial thromboembolism was 0.6% (n=154 [95% CI, 0.6%-0.8%]), 1.4% (n=16 [95% CI, 0.8%-2.2%]), 1.9% (n=141 [95% CI, 1.6%-2.2%]), 1.7% (n=12 [95% CI, 0.9%-2.9%]), 2.0% (n=13 [95% CI, 1.1%-3.4%]), 2.3% (n=187 [95% CI, 2.0%-2.7%]), and 4.4% (n=533 [95% CI, 4.1%-4.8%]) for CHA2DS2-VASc 0, heart failure, hypertension, diabetes, vascular disease, age 65 to 74 years (CHA2DS2-VASc 1), and age ≥75 years (CHA2DS2-VASc 2), respectively. No statistically significant difference was identified among subgroups of CHA2DS2-VASc 1 (P=0.15 for difference). CONCLUSIONS: For patients with atrial fibrillation, all subgroups of CHA2DS2-VASc 1 were associated with lower incidence of arterial thromboembolism compared with age ≥75 years without other risk factors (ie, CHA2DS2-VASc 2) and a higher incidence compared with CHA2DS2-VASc 0. No statistically significant difference was identified between the subgroups of CHA2DS2-VASc 1. These findings support current recommendations that patients within this intermediate risk group could be identified with a similar risk of arterial thromboembolism.

Clinical Outcomes With Electronic Nudges to Increase Influenza Vaccination : A Prespecified Analysis of a Nationwide, Pragmatic, Registry-Based, Randomized Implementation Trial.

BACKGROUND: In the NUDGE-FLU (Nationwide Utilization of Danish Government Electronic letter system for increasing inFLUenza vaccine uptake) trial, electronic letters incorporating cardiovascular (CV) gain-framing and repeated messaging increased influenza vaccination by approximately 1 percentage point. OBJECTIVE: To evaluate the effects of the successful nudging interventions on downstream clinical outcomes. DESIGN: Prespecified exploratory analysis of a nationwide randomized implementation trial. (ClinicalTrials.gov: NCT05542004). SETTING: The 2022 to 2023 influenza season. PARTICIPANTS: 964 870 Danish citizens aged 65 years or older. INTERVENTION: Usual care or 9 different electronically delivered behavioral nudging letters. MEASUREMENTS: Cardiovascular, respiratory, and other clinical end points during follow-up from intervention delivery (16 September 2022) through 31 May 2023. RESULTS: The analysis set included 691 820 participants. Hospitalization for pneumonia or influenza occurred in 3354 of 346 327 (1.0%) participants in the usual care group, 396 of 38 586 (1.0%) in the CV gain-framing group (hazard ratio [HR], 1.06 [95% CI, 0.95 to 1.18]; versus usual care), and 403 of 38 231 (1.1%) in the repeated letter group (HR, 1.09 [CI, 0.98 to 1.21]; versus usual care). In the usual care group, 44 682 (12.9%) participants were hospitalized for any cause, compared with 5002 (13.0%) in the CV gain-framing group (HR, 1.00 [CI, 0.97 to 1.03]; versus usual care) and 4965 (13.0%) in the repeated letter group (HR, 1.01 [CI, 0.98 to 1.04]; versus usual care). A total of 6341 (1.8%) participants died in the usual care group, compared with 721 (1.9%) in the CV gain-framing group (HR, 1.02 [CI, 0.94 to 1.10]; versus usual care) and 646 (1.7%) in the repeated letter group (HR, 0.92 [CI, 0.85 to 1.00]; versus usual care). LIMITATION: Prespecified but exploratory analysis, potential misclassification of events in routinely collected registry data, and results may not be generalizable to other health systems or countries with other racial compositions and/or cultural or societal norms. CONCLUSION: In a prespecified exploratory analysis, modest increases in influenza vaccination rates seen with electronic nudges did not translate into observable improvements in clinical outcomes. Seasonal influenza vaccination should remain strongly recommended. PRIMARY FUNDING SOURCE: Sanofi.

Atrial fibrillation: age at diagnosis, incident cardiovascular events, and mortality.

BACKGROUND AND AIMS: Patients with atrial fibrillation (AF) are at increased risks of cardiovascular diseases and mortality, but risks according to age at diagnosis have not been reported. This study investigated age-specific risks of outcomes among patients with AF and the background population. METHODS: This nationwide population-based cohort study included patients with AF and controls without outcomes by the application of exposure density matching on the basis of sex, year of birth, and index date. The absolute risks and hazard rates were stratified by age groups and assessed using competing risk survival analyses and Cox regression models, respectively. The expected differences in residual life years among participants were estimated. RESULTS: The study included 216 579 AF patients from year 2000 to 2020 and 866 316 controls. The mean follow-up time was 7.9 years. Comparing AF patients with matched controls, the hazard ratios among individuals ≤50 years was 8.90 [95% confidence interval (CI), 7.17-11.0] for cardiomyopathy, 8.64 (95% CI, 7.74-9.64) for heart failure, 2.18 (95% CI, 1.89-2.52) for ischaemic stroke, and 2.74 (95% CI, 2.53-2.96) for mortality. The expected average loss of life years among individuals ≤50 years was 9.2 years (95% CI, 9.0-9.3) years. The estimates decreased with older age. CONCLUSIONS: The findings show that earlier diagnosis of AF is associated with a higher hazard ratio of subsequent myocardial disease and shorter life expectancy. Further studies are needed to determine causality and whether AF could be used as a risk marker among particularly younger patients.

Gut Microbiota Alterations and Circulating Imidazole Propionate Levels Are Associated With Obstructive Coronary Artery Disease in People With HIV.

BACKGROUND: The impact of gut microbiota and its metabolites on coronary artery disease (CAD) in people with human immunodeficiency virus (PWH) is unknown. Emerging evidence suggests that imidazole propionate (ImP), a microbial metabolite, is linked with cardiometabolic diseases. METHODS: Fecal samples from participants of the Copenhagen Comorbidity in HIV infection (COCOMO) study were processed for 16S rRNA sequencing and ImP measured with liquid chromatography-tandem mass spectrometry. CAD severity was investigated by coronary computed tomography-angiography, and participants grouped according to obstructive CAD (n = 60), nonobstructive CAD (n = 80), or no CAD (n = 114). RESULTS: Participants with obstructive CAD had a gut microbiota with lower diversity and distinct compositional shift, with increased abundance of Rumiococcus gnavus and Veillonella, known producers of ImP. ImP plasma levels were associated with this dysbiosis, and significantly elevated in participants with obstructive CAD. However, gut dysbiosis but not plasma ImP was independently associated with obstructive CAD after adjustment for traditional and HIV-related risk factors (adjusted odds ratio, 2.7; 95% confidence interval, 1.1-7.2; P = .048). CONCLUSIONS: PWH with obstructive CAD displays a distinct gut microbiota profile and increased circulating ImP plasma levels. Future studies should determine whether gut dysbiosis and related metabolites such as ImP are predictive of incident cardiovascular events.

Long-Term Incidence of Ischemic Stroke After Transient Ischemic Attack: A Nationwide Study From 2014 to 2020.

BACKGROUND: The short-term incidence of ischemic stroke after a transient ischemic attack (TIA) is high. However, data on the long-term incidence are not well known but are needed to guide preventive strategies. METHODS: Patients with first-time TIA (index date) in the Danish Stroke Registry (January 2014-December 2020) were included and matched 1:4 with individuals from the background population and 1:1 with patients with a first-time ischemic stroke on the basis of age, sex, and calendar year. The incidences of ischemic stroke and mortality from index date were estimated by Aalen-Johansen and Kaplan-Meier estimators, respectively, and compared between groups using multivariable Cox regression. RESULTS: We included 21 500 patients with TIA, 86 000 patients from the background population, and 21 500 patients with ischemic stroke (median age, 70.8 years [25th-75th percentile, 60.8-78.7]; 53.1% males). Patients with TIA had more comorbidities than the background population, yet less than the control stroke population. The 5-year incidence of ischemic stroke after TIA (6.1% [95% CI, 5.7-6.5]) was higher than the background population (1.5% [95% CI, 1.4-1.6], P<0.01; hazard ratio, 5.14 [95% CI, 4.65-5.69]) but lower than the control stroke population (8.9% [95% CI, 8.4-9.4], P<0.01; hazard ratio, 0.58 [95% CI, 0.53-0.64]). The 5-year mortality for patients with TIA (18.6% [95% CI, 17.9-19.3]) was higher than the background population (14.8% [95% CI, 14.5-15.1], P<0.01; hazard ratio, 1.26 [95% CI, 1.20-1.32]) but lower than the control stroke population (30.1% [95% CI, 29.3-30.9], P<0.01; hazard ratio, 0.41 [95% CI, 0.39-0.44]). CONCLUSIONS: Patients with first-time TIA had an ischemic stroke incidence of 6.1% during the 5-year follow-up period. After adjustment for relevant comorbidities, this incidence was approximately 5-fold higher than what was found for controls in the background population and 40% lower than for patients with recurrent ischemic stroke.

Effects of Atrial Fibrillation Screening According to N-Terminal Pro-B-Type Natriuretic Peptide: A Secondary Analysis of the Randomized LOOP Study.

BACKGROUND: Research suggests NT-proBNP (N-terminal pro-B-type natriuretic peptide) to be a strong predictor of incident atrial fibrillation (AF) and stroke. However, its utility in AF screening remains unknown. The aim of this study was to investigate NT-proBNP as a potential marker for screening efficacy with respect to AF yield and stroke prevention. METHODS: In the LOOP Study (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals), 6004 AF-naïve individuals at least 70 years old and with additional stroke risk factors were randomized 1:3 to either screening with an implantable loop recorder (ILR) and initiation of anticoagulation upon detection of AF episodes lasting ≥6 minutes or usual care (control). This post hoc analysis included study participants with available NT-proBNP measurement at baseline. RESULTS: A total of 5819 participants (96.9% of the trial population) were included. The mean age was 74.7 years (SD, 4.1 years) and 47.5% were female. The median NT-proBNP level was 15 pmol/L (interquartile range, 9-28 pmol/L) corresponding to 125 pg/mL (interquartile range, 76-233 pg/mL). NT-proBNP above median was associated with an increased risk of AF diagnosis both in the ILR group (hazard ratio, 1.84 [95% CI, 1.51-2.25]) and the control group (hazard ratio, 2.79 [95% CI, 2.30-3.40]). Participants with NT-proBNP above the median were also at higher risk of clinical events compared with those having lower levels (hazard ratio, 1.21 [95% CI, 0.96-1.54] for stroke or systemic embolism [SE], 1.60 [95% CI, 1.32-1.95] for stroke/SE/cardiovascular death, and 1.91 [95% CI, 1.61-2.26] for all-cause death). Compared with usual care, ILR screening was associated with significant reductions in stroke/SE and stroke/SE/cardiovascular death among participants with NT-proBNP above median (hazard ratio, 0.60 [95% CI, 0.40-0.90] and 0.70 [95% CI, 0.53-0.94], respectively) but not among those with lower levels (Pinteraction=0.029 for stroke/SE and 0.045 for stroke/SE/cardiovascular death). No risk reduction in all-cause death was observed in either NT-proBNP subgroup for ILR versus control (Pinteraction=0.68). Analyzing NT-proBNP as a continuous variable yielded similar findings. CONCLUSIONS: In an older population with additional stroke risk factors, ILR screening for AF was associated with a significant reduction in stroke risk among individuals with higher NT-proBNP levels but not among those with lower levels. These findings should be considered hypothesis generating and warrant further study before clinical implementation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02036450.

Effect of Electronic Nudges on Influenza Vaccination Rate in Older Adults With Cardiovascular Disease: Prespecified Analysis of the NUDGE-FLU Trial.

BACKGROUND: Influenza vaccines have been demonstrated to effectively reduce the incidence of influenza infection and potentially associated risks of cardiovascular events in patients with cardiovascular disease (CVD). Despite strong guideline and public health endorsements, global influenza vaccination rates in patients with CVD are highly variable. This prespecified analysis of NUDGE-FLU (Nationwide Utilization of Danish Government Electronic Letter System for Increasing Influenza Vaccine Uptake) examined the effect of digital behavioral nudges on influenza vaccine uptake based on the presence of CVD. METHODS: NUDGE-FLU was a randomized, pragmatic, nationwide, register-based trial that included Danish citizens 65 years of age or older during the 2022 to 2023 influenza season. Households were randomized in a 9:1:1:1:1:1:1:1:1:1 ratio to usual care or 9 electronic letters with designs based on behavioral concepts. Danish nationwide registers were used to collect baseline and outcome data. The primary end point was receipt of an influenza vaccine on or before January 1, 2023. The effects of the intervention letters were examined according to the presence of CVD and across cardiovascular subgroups that included heart failure, ischemic heart disease, and atrial fibrillation. RESULTS: Of 964 870 NUDGE-FLU participants from 691 820 households, 264 392 (27.4%) had CVD. During follow-up, 83.1% of participants with CVD versus 79.2% of participants without CVD received an influenza vaccination (P<0.001). Compared with usual care, a letter emphasizing the potential cardiovascular benefits of influenza vaccination increased vaccination rates; this effect was consistent in participants with CVD (absolute difference, +0.60 percentage points [99.55% CI, -0.48 to 1.68]) and without CVD (+0.98 percentage points [99.55% CI, 0.27-1.70; P for interaction=0.41). A repeated letter strategy with a reminder follow-up letter 14 days later was also effective in increasing influenza vaccination, irrespective of CVD (CVD: absolute difference, +0.80 percentage points [99.55% CI, -0.27 to 1.86]; no CVD: +0.67 percentage points [99.55% CI, -0.06 to 1.40]; P for interaction=0.77). Effectiveness of both nudging strategies was consistent across all major CVD subgroups. None of the other 7 nudging strategies were effective, regardless of CVD status. CONCLUSIONS: Electronic letter interventions emphasizing the potential cardiovascular benefits of influenza vaccination and using a reminder letter strategy were similarly beneficial in increasing influenza vaccination rates among older adults with and without CVD and across cardiovascular subgroups. Electronic nudges may improve influenza vaccine uptake in individuals with CVD. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT05542004.

Endothelin-1, Outcomes in Patients With Heart Failure and Reduced Ejection Fraction, and Effects of Dapagliflozin: Findings From DAPA-HF.

BACKGROUND: ET-1 (endothelin-1) is implicated in the pathophysiology of heart failure and renal disease. Its prognostic importance and relationship with kidney function in patients with heart failure with reduced ejection fraction receiving contemporary treatment are uncertain. We investigated these and the efficacy of dapagliflozin according to ET-1 level in the DAPA-HF trial (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure). METHODS: We investigated the incidence of the primary outcome (cardiovascular death or worsening heart failure), change in kidney function, and the effect of dapagliflozin according to baseline ET-1 concentration, adjusting in Cox models for other recognized prognostic variables in heart failure including NT-proBNP (N-terminal pro-B-type natriuretic peptide). We also examined the effect of dapagliflozin on ET-1 level. RESULTS: Overall, 3048 participants had baseline ET-1 measurements: tertile 1 (T1; ≤3.28 pg/mL; n=1016); T2 (>3.28-4.41 pg/mL; n=1022); and T3 (>4.41 pg/mL; n=1010). Patients with higher ET-1 were more likely male, more likely obese, and had lower left ventricular ejection fraction, lower estimated glomerular filtration rate, worse functional status, and higher NT-proBNP and hs-TnT (high-sensitivity troponin-T). In the adjusted Cox models, higher baseline ET-1 was independently associated with worse outcomes and steeper decline in kidney function (adjusted hazard ratio for primary outcome of 1.95 [95% CI, 1.53-2.50] for T3 and 1.36 [95% CI, 1.06-1.75] for T2; both versus T1; estimated glomerular filtration rate slope: T3, -3.19 [95% CI, -3.66 to -2.72] mL/min per 1.73 m2 per y, T2, -2.08 [95% CI, -2.52 to -1.63] and T1 -2.35 [95% CI, -2.79 to -1.91]; P=0.002). The benefit of dapagliflozin was consistent regardless of baseline ET-1, and the placebo-corrected decrease in ET-1 with dapagliflozin was 0.13 pg/mL (95% CI, 0.25-0.01; P=0.029). CONCLUSIONS: Higher baseline ET-1 concentration was independently associated with worse clinical outcomes and more rapid decline in kidney function. The benefit of dapagliflozin was consistent across the range of ET-1 concentrations measured, and treatment with dapagliflozin led to a small decrease in serum ET-1 concentration. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03036124.

Sex Differences in Characteristics, Outcomes, and Treatment Response With Dapagliflozin Across the Range of Ejection Fraction in Patients With Heart Failure: Insights From DAPA-HF and DELIVER.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors have emerged as a key pharmacotherapy in heart failure (HF) with both reduced and preserved ejection fraction. The benefit of other HF therapies may be modified by sex, but whether sex modifies the treatment effect and safety profile of sodium-glucose cotransporter-2 inhibitors remains unclear. Our analyses aim to assess the effect of sex on the efficacy and safety of dapagliflozin. METHODS: In a prespecified patient-level pooled analysis of DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure), clinical outcomes were compared by sex (including the composite of cardiovascular death or worsening HF events, cardiovascular death, all-cause death, total events [first and recurrent HF hospitalization and cardiovascular death], and Kansas City Cardiomyopathy Questionnaire scores) across the spectrum of left ventricular ejection fraction. RESULTS: Of a total of 11 007 randomized patients, 3856 (35%) were women. Women with HF were older and had higher body mass index but were less likely to have a history of diabetes and myocardial infarction or stroke and more likely to have hypertension and atrial fibrillation compared with men. At baseline, women had higher ejection fraction but worse Kansas City Cardiomyopathy Questionnaire scores than men did. After adjustment for baseline differences, women were less likely than men to experience cardiovascular death (adjusted hazard ratio, 0.69 [95% CI, 0.60-0.79]), all-cause death (adjusted hazard ratio, 0.69 [95% CI, 0.62-0.78]), HF hospitalizations (adjusted hazard ratio, 0.82 [95% CI, 0.72-0.94]), and total events (adjusted rate ratio, 0.77 [95% CI, 0.71-0.84]). Dapagliflozin reduced the primary end point in both men and women similarly (Pinteraction=0.77) with no sex-related differences in secondary outcomes (all Pinteraction>0.35) or safety events. The benefit of dapagliflozin was observed across the entire ejection fraction spectrum and was not modified by sex (Pinteraction>0.40). There were no sex-related differences in serious adverse events, adverse events, or drug discontinuation attributable to adverse events. CONCLUSIONS: In DAPA-HF and DELIVER, the response to dapagliflozin was similar between men and women. Sex did not modify the treatment effect of dapagliflozin across the range of ejection fraction.

Electronic nudges to increase influenza vaccination uptake in Denmark: a nationwide, pragmatic, registry-based, randomised implementation trial.

BACKGROUND: Influenza vaccination rates remain suboptimal despite effectiveness in preventing influenza infection and related complications. We investigated whether behavioural nudges, delivered via a governmental electronic letter system, would increase influenza vaccination uptake among older adults in Denmark. METHODS: We did a nationwide, pragmatic, registry-based, cluster-randomised implementation trial during the 2022-23 influenza season in Denmark. All Danish citizens aged 65 years or older or turning 65 years by Jan 15, 2023 were included. We excluded individuals living in nursing homes and individuals who had an exemption from the Danish mandatory governmental electronic letter system. Households were randomly assigned (9:1:1:1:1:1:1:1:1:1) to usual care or nine different electronic letters designed on the basis of different behavioural nudging concepts. Data were sourced from nationwide Danish administrative health registries. The primary endpoint was receipt of influenza vaccination on or before Jan 1, 2023. The primary analysis assessed an analytical set of one randomly selected individual per household, and a sensitivity analysis included all randomly assigned individuals and accounted for within-household correlation. The trial is registered with ClinicalTrials.gov, NCT05542004. FINDINGS: We identified 1 232 938 individuals aged 65 years or older in Denmark and excluded 56 436 (4·6%) individuals living in nursing homes and 211 632 (17·2%) with an exemption from the electronic letter system. We randomly assigned 964 870 (78·3%) participants across 691 820 households. Compared with usual care, influenza vaccination rates were higher in the group receiving an electronic letter highlighting potential cardiovascular benefits of vaccination (81·00% vs 80·12%; difference 0·89 percentage points [99·55% CI 0·29-1·48]; p<0·0001) and the group receiving repeated letters at randomisation and at day 14 (80·85% vs 80·12%; difference 0·73 percentage points [0·13-1·34]; p=0·0006). These strategies improved vaccination rates across major subgroups including those with and without established cardiovascular disease. The cardiovascular gain-framed letter was particularly effective among participants who had not been vaccinated for influenza in the previous season (pinteraction=0·0002). A sensitivity analysis of all randomly assigned individuals accounting for within-household clustering yielded similar findings. INTERPRETATION: Electronically delivered letters highlighting potential cardiovascular benefits of influenza vaccination or sent again as a reminder significantly increased vaccination uptake across Denmark. Although the magnitude of effectiveness was modest, the low-touch, inexpensive, and highly scalable nature of these electronic letters might be informative for future public health campaigns. FUNDING: Sanofi.

Angiotensin Receptor-Neprilysin Inhibition in Acute Myocardial Infarction.

BACKGROUND: In patients with symptomatic heart failure, sacubitril-valsartan has been found to reduce the risk of hospitalization and death from cardiovascular causes more effectively than an angiotensin-converting-enzyme inhibitor. Trials comparing the effects of these drugs in patients with acute myocardial infarction have been lacking. METHODS: We randomly assigned patients with myocardial infarction complicated by a reduced left ventricular ejection fraction, pulmonary congestion, or both to receive either sacubitril-valsartan (97 mg of sacubitril and 103 mg of valsartan twice daily) or ramipril (5 mg twice daily) in addition to recommended therapy. The primary outcome was death from cardiovascular causes or incident heart failure (outpatient symptomatic heart failure or heart failure leading to hospitalization), whichever occurred first. RESULTS: A total of 5661 patients underwent randomization; 2830 were assigned to receive sacubitril-valsartan and 2831 to receive ramipril. Over a median of 22 months, a primary-outcome event occurred in 338 patients (11.9%) in the sacubitril-valsartan group and in 373 patients (13.2%) in the ramipril group (hazard ratio, 0.90; 95% confidence interval [CI], 0.78 to 1.04; P = 0.17). Death from cardiovascular causes or hospitalization for heart failure occurred in 308 patients (10.9%) in the sacubitril-valsartan group and in 335 patients (11.8%) in the ramipril group (hazard ratio, 0.91; 95% CI, 0.78 to 1.07); death from cardiovascular causes in 168 (5.9%) and 191 (6.7%), respectively (hazard ratio, 0.87; 95% CI, 0.71 to 1.08); and death from any cause in 213 (7.5%) and 242 (8.5%), respectively (hazard ratio, 0.88; 95% CI, 0.73 to 1.05). Treatment was discontinued because of an adverse event in 357 patients (12.6%) in the sacubitril-valsartan group and 379 patients (13.4%) in the ramipril group. CONCLUSIONS: Sacubitril-valsartan was not associated with a significantly lower incidence of death from cardiovascular causes or incident heart failure than ramipril among patients with acute myocardial infarction. (Funded by Novartis; PARADISE-MI ClinicalTrials.gov number, NCT02924727.).

Temporal changes in the number of European and American guideline recommendations and underlying evidence base for the management of infective: An update of previous published data.

This report aimed to examine temporal changes in the number of recommendations on management of infective endocarditis in the European and American guidelines. The number of recommendations has increased since 2004 without an increment in evidence base in the European iteration. American guidelines have reduced the number of recommendations with a main evidence base of level B.

High-risk admission prior to transcatheter aortic valve replacement and subsequent outcomes.

BACKGROUND: Severe, symptomatic aortic stenosis may cause heart failure, acute myocardial infarction, or syncope; limited data exist on the occurrence of such events before transcatheter aortic valve replacement (TAVR) and their impact on subsequent outcomes. Thus, we investigated the association between a preceding event and outcomes after TAVR. METHODS: From 2014 to 2021 all Danish patients who underwent TAVR were included. Preceding events up to 180 days before TAVR were identified. A preceding event was defined as a hospitalization for heart failure, acute myocardial infarction, or syncope. The 1-year risk of all-cause death, and cardiovascular or all-cause hospitalization was compared for patients with versus without a preceding event using Kaplan-Meier, Aalen-Johansen, and in Cox regression analyses adjusted for patient characteristics. RESULTS: Of 5,851 patients included, 759 (13.0%) had a preceding event. The median age was 81 years in both groups. Male sex and frailty were more prevalent in patients with a preceding event (males: 64.7% vs 55.2%, frailty: 49.6% vs 40.6%). The most common type of preceding event was a hospitalization for heart failure (n = 524). For patients with a preceding event, the 1-year risk of death was 11.7% (95% CI: 9.4%-14.1%) versus 8.0% (95% CI: 7.2%-8.7%) for patients without. The corresponding adjusted hazard ratio (aHR) was 1.29 (95%CI: 1.01-1.64). Mortality was highest for patients with a preceding event of a heart failure admission (1-year risk: 13.5% [95%CI: 10.5%-16.5%]). Comparing patients with a preceding event to those without, the 1-year risk for cardiovascular rehospitalization was 15.0% versus 8.2% (aHR 1.60 [95%CI: 1.29-1.99]) and 57.6% versus 50.6% for all-cause rehospitalization (aHR 1.08 [95%CI: 0.87-1.20]). CONCLUSIONS: A hospitalization for heart failure, myocardial infarction, or syncope prior to TAVR was associated with a poorer prognosis and could represent a group to focus resource management on. Interventions to prevent preceding events and improvements in pre- and post-TAVR optimization of these patients are warranted.

Patient characteristics, treatment patterns, and prognosis in drug-use-associated infective endocarditis in Denmark from 1999 to 2018.

BACKGROUND: While the proportion of drug-use-associated infective endocarditis (DU-IE) has been increasing during the opioid crisis in the United States, it is unknown whether this is seen in Denmark, where several preventive means have been implemented. We aimed to assess the temporal proportion of DU-IE and examine the rate of IE recurrence and mortality. METHODS: This nationwide cohort study identified all patients with first-time infective endocarditis in 1999-2018. Drug use was defined using ICD-8/10 codes or prescription filling of medication for opioid use disorder. Long-term mortality was examined with a Kaplan-Meier estimator and a multivariate Cox model. The recurrence of IE was examined with the Aalen-Johansen method and a multivariate cause-specific hazard model. RESULTS: We included 8,843 patients with IE: 407 with DU-IE (60.7% male, median age 43.8 years) and 8,436 with non-DU-IE (65.8% male, median age 71.5 years). The proportion of DU-IE decreased from 5.9% to 3.8% during our study period. The one-year cumulative incidence of all-cause mortality was 16.9% (CI 12.9%-20.8%) for patients with DU-IE and 17.3% (CI 16.4%-18.2%) for patients with non-DU-IE. Drug use was associated with higher one-year mortality (adjusted HR 1.64 (CI 1.23%-2.21%)). The 1-year cumulative incidence of IE recurrence was 12.8% (CI 9.3%-16.3%) in patients with DU-IE and 4.3% (CI 3.8%-4.8%) in patients with non-DU-IE. Drug use was associated with a higher 1-year recurrence of IE (adjusted HR 3.39 (CI 2.35-4.88)). CONCLUSION: In Denmark, the proportion of patients with DU-IE fell by one-third from 1999 to 2018. DU-IE was associated with higher mortality and recurrence rates than non-DU-IE.

NatIonal Danish endocarditis stUdieS - Design and objectives of the NIDUS registry.

AIMS: The NatIonal Danish endocarditis stUdieS (NIDUS) registry aims to investigate the mechanisms contributing to the increasing incidence of infective endocarditis (IE) and to discover risk factors associated to the course, treatment and clinical outcomes of the disease. METHODS: The NIDUS registry was created to investigate a nationwide unselected group of patients hospitalized for IE. The National Danish healthcare registries have been queried for validated IE diagnosis codes (International Classification of Disease, 10th edition [ICD-10]: DI33, DI38, and DI398). Subsequently, a team of 28 healthcare professionals, including experts in endocarditis, will systematically review and evaluate all identified patient records using the modified Duke Criteria and the 2015 European Society of Cardiology modified diagnostic criteria. The registry will contain all cases with definite or possible IE found in primary data sources in Denmark between January 1, 2016, and December 31, 2021. We will gather individual patient data, such as clinical, microbiological, and echocardiographic characteristics, treatment regimens, and clinical outcomes. A digital data collection form will be used to the gathering of data. A sample of approximately 4,300 individual patients will be evaluated using primary data sources. CONCLUSIONS AND PERSPECTIVES: The NIDUS registry will be the first comprehensive nationwide IE registry, contributing critical knowledge about the course, treatment, and clinical outcomes of the disease. Additionally, it will significantly aid in identifying areas in which future research is needed.

Rationale and design of NUDGE-FLU-CHRONIC and NUDGE-FLU-2: Two nationwide randomized trials of electronic nudges to increase influenza vaccination among patients with chronic diseases and older adults during the 2023/2024 influenza season.

BACKGROUND: Yearly influenza vaccination is strongly recommended for older adults and patients with chronic diseases including cardiovascular disease (CVD); however, vaccination rates remain suboptimal, particularly among younger patients. Electronic letters incorporating behavioral nudges are highly scalable public health interventions which can potentially increase vaccination, but further research is needed to determine the most effective strategies and to assess effectiveness across different populations. The purpose of NUDGE-FLU-CHRONIC and NUDGE-FLU-2 are to evaluate the effectiveness of electronic nudges delivered via the Danish governmental electronic letter system in increasing influenza vaccination among patients with chronic diseases and older adults, respectively. METHODS: Both trials are designed as pragmatic randomized implementation trials enrolling all Danish citizens in their respective target groups and conducted during the 2023/2024 influenza season. NUDGE-FLU-CHRONIC enrolls patients aged 18-64 years with chronic diseases. NUDGE-FLU-2 builds upon the NUDGE-FLU trial conducted in 2022/2023 and aims to expand the evidence by testing both previously successful and new nudges among adults ≥65 years during a subsequent influenza season. Persons with exemptions from the electronic letter system are excluded from both trials. In both trials, participants are randomized in a 2.45:1:1:1:1:1:1 ratio to either receive no electronic letter (usual care) or to receive one of 6 different behaviorally informed electronic letters. NUDGE-FLU-CHRONIC has randomized 299,881 participants with intervention letters delivered on September 24, 2023, while NUDGE-FLU-2 has randomized 881,373 participants and delivered intervention letters on September 13, 2023. Follow-up is currently ongoing. In both trials, the primary endpoint is receipt of influenza vaccination on or before January 1, 2024, and the secondary endpoint is time to vaccination. Clinical outcomes including respiratory and cardiovascular hospitalizations, all-cause hospitalization, and mortality are included as prespecified exploratory endpoints. Prespecified individual-level pooled analyses will be conducted across NUDGE-FLU, NUDGE-FLU-CHRONIC, and NUDGE-FLU-2. DISCUSSION: NUDGE-FLU-CHRONIC is the first nationwide randomized trial of electronic nudges to increase influenza vaccination conducted among 18-64-year-old high-risk patients with chronic diseases. NUDGE-FLU-2 will provide further evidence on the effectiveness of electronic nudges among older adults ≥65 years. Collectively, the NUDGE-FLU trials will provide an extensive evidence base for future public health communications. TRIAL REGISTRATION: NUDGE-FLU-CHRONIC: Clinicaltrials.gov: NCT06030739, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030739. NUDGE-FLU-2: Clinicaltrials.gov: NCT06030726, registered September 11, 2023, https://clinicaltrials.gov/study/NCT06030726.

Empagliflozin to elderly and obese patients with increased risk of developing heart failure: Study protocol for the Empire Prevent trial program.

INTRODUCTION: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have previously demonstrated cardioprotective properties in patients with type 2 diabetes, suggesting a preventive effect on heart failure (HF). The Empire Prevent trial program investigates the therapeutic potential for HF prevention by evaluating the cardiac, metabolic, and renal effects of the SGLT2 inhibitor empagliflozin in patients with increased risk of developing HF, but without diabetes or established HF. METHODS: The Empire Prevent trial program is an investigator-initiated, double-blind, randomized clinical trial program including elderly and obese patients (60-84 years, body mass index >28 kg/m2) with at least one manifestation of hypertension, cardiovascular or chronic kidney disease, but no history of diabetes or HF. The aims are to investigate the effects of empagliflozin on 1) physical capacity and left ventricular and atrial structural changes with peak oxygen consumption and left ventricular mass as primary endpoints (Empire Prevent Cardiac), and 2) cardiac-adipose tissue interaction and volume homeostasis with primary endpoints of changes in epicardial adipose tissue and estimated extracellular volume (Empire Prevent Metabolic). At present, 138 of 204 patients have been randomized in the Empire Prevent trial program. Patients are randomized 1:1 to 180 days treatment with empagliflozin 10 mg daily or placebo, while undergoing a comprehensive examination program at baseline and follow-up. DISCUSSION: The Empire Prevent trial program will mark the first step towards elucidating the potential of SGLT2 inhibition for HF prevention in an outpatient setting in elderly and obese patients with increased risk of developing HF, but with no history of diabetes or established HF. Furthermore, the Empire Prevent trial program will supplement the larger event-driven trials by providing mechanistic insights to the beneficial effects of SGLT2 inhibition. TRIAL REGISTRATION: Both parts of the trial program have been registered on September 13th 2021 (Clinical Trial Registration numbers: NCT05084235 and NCT05042973) before enrollment of the first patient. All patients will provide oral and written informed consent. The trial is approved by The Regional Committee on Health Research Ethics and the Danish Medicines Agency. Data will be disseminated through scientific meetings and peer-reviewed journals irrespective of outcome.

Effect of Implantable Cardioverter-defibrillators in Nonischemic Heart Failure According to Background Medical Therapy: Extended Follow-up of the DANISH Trial.

BACKGROUND: The Heart Failure Collaboratory (HFC) score integrates types and dosages of guideline-directed pharmacotherapies for heart failure (HF) with reduced ejection fraction (HFrEF). We examined the effects of cardioverter-defibrillator (ICD) implantation according to the modified HFC (mHFC) score in 1116 patients with nonischemic HFrEF from the Danish Study to Assess the Efficacy of ICDs in Patients with Nonischemic Systolic HF on Mortality (DANISH). METHODS AND RESULTS: Patients were assigned scores for renin-angiotensin-system inhibitors, beta-blockers and mineralocorticoid receptor antagonists (0, no use; 1, < 50% of maximum dosage; 2, ≥ 50% of maximum dosage). The maximum score was 6, corresponding to ≥ 50% of maximum dosage for all therapies. The median baseline mHFC score was 4, and the median follow-up was 9.5 years. Compared with an mHFC score of 3-4, an mHFC score of 1-2 was associated with a higher rate of all-cause death (mHFC = 1-2: adjusted HR 1.67 [95% CI, 1.23-2.28]; mHFC = 3-4, reference; mHFC = 5-6: adjusted HR 1.07 [95% CI, 0.87-1.31]). ICD implantation did not reduce all-cause death compared with control (reference) (HR 0.89 [95% CI, 0.74-1.08]), regardless of mHFC score (mHFC = 1-2: HR 0.98 [95% CI, 0.56-1.71]; mHFC = 3-4: HR 0.89 [95% CI,0.66-1.20]; mHFC = 5-6: HR 0.85 [95% CI, 0.64-1.12]; Pinteraction, 0.65). Similarly, ICD implantation did not reduce cardiovascular death (HR 0.87 [95% CI, 0.70-1.09]), regardless of mHFC score (Pinteraction, 0.59). The ICD group had a lower rate of sudden cardiovascular death (HR, 0.60 [95% CI,0.40-0.92]); this association was not modified by mHFC score (Pinteraction, 0.35). CONCLUSIONS: Lower mHFC scores were associated with higher rates of all-cause death. ICD implantation did not result in an overall survival benefit in patients with nonischemic HFrEF, regardless of mHFC score.